1. Field of the Invention
The present invention is directed to a novel polymorphic form of olopatadine hydrochloride, and to novel methods for producing olopatadine, and pharmaceutically acceptable salts thereof.
2. Background and Related Art
Olopatadine-HCl ([(Z)-3-(dimethylamino)propylidene]-6,11-dihydrodibenz[b,e]oxepin-2-acetic acid hydrochloride) is a selective histamine H1-receptor antagonist that is used for the treatment of ocular symptoms of seasonal allergic conjunctivitis. The compound may be administered in a solid oral dosage form or as an ophthalmic solution.

Olopatadine is stated to be an effective treatment for symptoms of allergic rhinitis and urticaria (e.g., sneezing, nasal discharge and nasal congestion), as well as in the treatment of various skin diseases, such as eczema and dermatitis.
Olopatadine and its pharmaceutically acceptable salts are disclosed in EP 0214779, U.S. Pat. No. 4,871,865, EP 0235796 and U.S. Pat. No. 5,116,863. There are two general routes for the preparation of olopatadine which are described in EP 0214779: One involves a Wittig reaction and the other involves a Grignard reaction followed by a dehydration step. A detailed description of the syntheses of olopatadine and its salts is also disclosed in Ohshima, E., et al., J. Med. Chem. 1992, 35, 2074-2084.
EP 0235796 describes a preparation of olopatadine derivatives starting from 11-oxo-6,11-dihydroxydibenz[b,e]oxepin-2-acetic acid, as well as the following three different synthetic routes for the preparation of corresponding dimethylaminopropyliden-dibenz[b,e]oxepin derivatives, as shown in schemes 1-3 below:



The syntheses of several corresponding tricyclic derivatives are disclosed in the same manner in EP 0214779, in which the Grignard addition (analogous to Scheme 1) and the Wittig reaction (analogous to Scheme 3) are described as key reactions.
The synthetic routes shown above in Schemes 2 and 3 for the preparation of olopatadine are also described in Ohshima, E., et al., J. Med. Chem. 1992, 35, 2074-2084 (schemes 4 and 5 below). In contrast to the above-identified patents, this publication describes the separation of the Z/E diastereomers (scheme 5).

A significant disadvantage of the synthetic route depicted in Scheme 4 is the diastereoselectivity of the dehydration step, which gives up to 90% of the undesired E-isomer. The last step (oxidation) is not described in this publication.
Scheme 5 below depicts a prior art method disclosed in Ohshima, E., et al., supra.

Each of the prior art methods for synthesis of olopatadine have significant cost and feasibility disadvantages. Specifically with the respect to the method set forth in Scheme 5, the disadvantages include:                (1) the need for excess reagents, e.g. 4.9 equivalents Wittig reagent and 7.6 equivalents of BuLi as the base for the Wittig reaction, which can be expensive;        (2) the need to use Wittig reagent in its hydrobromide salt form, so that additional amounts of the expensive and dangerous butyllithium reagent are necessary for the “neutralization” of the salt (i.e., excess butyllithium is required because of the neutralization);        (3) because 7.6 equivalents of the butyllithium are used (compared to 9.8 equivalents of the (Olo-IM4) Wittig reagent), the Wittig reagent is not converted completely to the reactive ylide form, and thus more than 2 equivalents of the Wittig reagent are wasted;        (4) the need for an additional esterification reaction after the Wittig reaction (presumably to facilitate isolation of the product from the reaction mixture) and the purification of the resulting oil by chromatography;        (5) the need to saponify the ester and to desalinate the reaction product (a diastereomeric mixture) with ion exchange resin, prior to separating the diastereomers;        (6) the need, after the separation of the diastereomers, and liberation of the desired diastereomer from its corresponding pTsOH salt, to desalinate the product (olopatadine) again with ion exchange resin;        (7) the formation of olopatadine hydrochloride from olopatadine is carried out using 8 N HCl in 2-propanol, which may esterify olopatadine and give rise to additional impurities and/or loss of olopatadine; and        (8) the overall yield of the olopatadine, including the separation of the diastereomers, is only approximately 24%, and the volume yield is less than 1%.        
As noted above, the known methods for preparing olopatadine in a Wittig reaction use the intermediate compounds 6,11-dihydro-11-oxo-dibenz[b,e]oxepin-2-acetic acid and 3-dimethylaminopropyltriphenylphosphonium bromide hydrobromide. Preparation of these chemical intermediates by prior art syntheses present a number of drawbacks that add to the cost and complexity of synthesizing olopatadine.
One known method for preparation of the compound 6,11-dihydro-11-oxo-dibenz[b,e]oxepin-2-acetic acid is depicted in Scheme 6, below. See also, U.S. Pat. No. 4,585,788; German patent publications DE 2716230, DE 2435613, DE 2442060, DE 2600768; Aultz, D. E., et al., J. Med. Chem. (1977), 20(1), 66-70; and Aultz, D. E., et al., J. Med. Chem. (1977), 20(11), 1499-1501.

In addition, U.S. Pat. No. 4,417,063 describes another method for the preparation of 6,11-dihydro-11-oxo-dibenz[b,e]oxepin-2-acetic acid, which is shown in Scheme 7.

Ueno, K., et al., J. Med. Chem. (1976), 19(7), 941, describes yet another prior art method for preparing 6,11-dihydro-11-oxo-dibenz[b,e]oxepin-2-acetic acid, which is shown below in Scheme 8.

Further, as depicted in Scheme 9, below, U.S. Pat. Nos. 4,118,401; 4,175,209; and 4,160,781 disclose another method for the synthesis of 6,11-dihydro-11-oxo-dibenz[b,e]oxepin-2-acetic acid.

JP 07002733 also describes the preparation of 6,11-dihydro-11-oxo-dibenz[b,e]oxepin-2-acetic acid, as follows in Scheme 10, below.

Specific methods and reagents for performing the intramolecular Friedel-Crafts reaction for cyclizing 4-(2-carboxybenzyloxy)-phenylacetic acid to form 6,11-dihydro-11-oxo-dibenz[b,e]oxepin-2-acetic acid are described in (1) EP 0068370 and DE 3125374 (cyclizations were carried out at reflux with acetyl chloride or acetic anhydride in the presence of phosphoric acid, in toluene, xylene or acetic anhydride as solvent); (2) EP 0069810 and U.S. Pat. No. 4,282,365 (cyclizations were carried out at 70-80° C. with trifluoroacetic anhydride in a pressure bottle); and (3) EP 0235796; U.S. Pat. No. 5,116,863 (cyclizations were carried out with trifluoroacetic anhydride in the presence of BF3.OEt2 and in methylene chloride as solvent).
Turning to the Wittig reagent for use in preparing olopatadine, 3-dimethylaminopropyltriphenylphosphonium bromide-hydrobromide and methods for its preparation are described in U.S. Pat. Nos. 3,354,155; 3,509,175; 5,116,863, and EP 0235796, and depicted in Scheme 11 below.

Corey, E. J., et al., Tetrahedron Letters, Vol. 26, No. 47, 5747-5748, 1985 describes a synthetic method for the preparation of 3-dimethylaminopropyltriphenylphosphonium bromide (free base), which is shown below in Scheme 12.

The prior art methods for preparing olopatadine and the chemical intermediates 6,11-dihydro-11-oxo-dibenz[b,e]oxepin-2-acetic acid, and 3-dimethylaminopropyltriphenylphosphonium bromide-hydrobromide (and its corresponding free base) are not desirable for synthesis of olopatadine on a commercial scale. For example, due to high reaction temperatures and the absence of solvents, the synthesis described in Ueno, K., et al., J. Med. Chem. (1976), 19(7), 941 and in U.S. Pat. No. 4,282,365 for preparation of the intermediate 4-(2-carboxybenzyloxy)phenylacetic acid is undesirable for a commercial scale process, although the synthesis described in JP 07002733, and set forth in Scheme 13 below, is carried out in an acceptable solvent.

The processes described in the literature for the intramolecular Friedel-Crafts acylation used to prepare 6,11-dihydro-11-oxo-dibenz[b,e]oxepin-2-acetic acid are undesirable for commercial scale synthesis because they generally require either drastic conditions in the high boiling solvents (e.g. sulfolane) or they require a two step synthesis with the corresponding acid chlorides as intermediate. Furthermore the procedures for synthesizing 6,11-dihydro-11-oxo-dibenz[b,e]oxepin-2-acetic acid as set forth in European patent documents EP 0069810 and EP 0235796 use excess trifluoroacetic anhydride (see Scheme 14), and are carried out without solvent in a pressure bottle at 70-80° C. (EP 0069810) or at room temperature in methylene chloride using catalytic amounts of BF3.Et2O (EP 0235796).

According to the teachings in EP 0235795, a suspension of 3-bromopropyltriphenylphosphonium bromide (Olo-IM4) in ethanol was reacted with 13.5 equivalents of an aqueous dimethylamine solution (50%) to provide dimethylaminopropyltriphenylphosphonium bromide HBr. After this reaction, the solvent was distilled off and the residue was recrystallized (yield: 59%).
U.S. Pat. No. 3,354,155 describes a reaction of 3-bromopropyltriphenylphosphonium bromide with 4.5 equivalents dimethylamine. The solution was concentrated and the residue was suspended in ethanol, evaporated and taken up in ethanol again. Gaseous hydrogen bromide was passed into the solution until the mixture was acidic. After filtration, the solution was concentrated, whereupon the product crystallized (yield of crude product: 85%). The crude product was recrystallized from ethanol.
A significant disadvantage of the prior art processes for making 3-dimethylaminopropyltriphenylphosphonium bromide hydrobromide involves the need for time consuming steps to remove excess dimethylamine, because such excess dimethylamine prevents crystallization of the reaction product. Thus, to obtain crystallization, the prior art processes require, for example, repeated evaporation of the reaction mixture (until dryness), which is undesirable for a commercial scale synthesis of olopatadine.
Corey, E. J., et al., Tetrahedron Letters, Vol. 26, No. 47, 5747-5748 (1985) describes the preparation of 3-dimethylaminopropyltriphenylphosphonium bromide (free base) from its corresponding hydrobromide salt. But the preparation of the free base, which uses an extraction step with methylene chloride as the solvent, is undesirable for commercial production because of the poor solubility of the free base in many of the organic solvents that are desirable for commercial production of chemical products, and because of the high solubility of the free base in water, causing low volume yields and loss of material. Furthermore according to this publication, the work up procedure gave an oil, which crystallized only after repeated evaporation in toluene.
It would be desirable to provide processes for preparing olopatadine on a large scale, e.g., on a commercial scale, in a manner that is cost efficient and provides olopatadine that has a low level of impurities, including a low level of the undesired diastereomer.
It further would be desirable to eliminate the need to derivatize the olopatadine product of the Wittig reaction, e.g., by esterification, in order to separate the olopatadine from the reaction mixture. It would be especially desirable to provide a method for preparing olopatadine that allows for isolation of olopatadine directly from the reaction mixture.
It would also be desirable to eliminate the need for the costly and dangerous base, butyllithium, that is used in previously described Wittig reactions for making olopatadine.
It would also be desirable to provide improved methods for preparing chemical intermediates used in the synthesis of olopatadine via a Wittig reaction.
In the description of the various aspects of applicants' invention that follows, reference may be made to the chemical intermediates, final products and byproducts in accordance with the nomenclature set forth immediately below.
The chemical names and structures for compounds that are discussed herein are set forth below in Table 1.
TABLE 1Structures, (chemical) names and abbreviationsAbbreviation forChemical name/structureChemical namePhthalideNone 4-Hydroxyphenylacetic acidNone 4-(2-Carboxybenzyloxy)-phenylacetic acidOlo-IM1 6,11-Dihydro-11-oxo-dibenz[b,e]oxepin-Olo-IM22-acetic acid TriphenylphosphineNone 1,3.DibromopropaneNone 3-Bromopropyl-Olo-IM3triphenylphosphonium bromide 3-Dimethylaminopropyl-Olo-IM4triphenylphosphonium bromidehydrobromide 3-Dimethylaminopropyl-Olo-IM4 (free base)triphenylphosphonium bromide 3-Dimethylamino-propylidene-Olo-IM4 ylidetriphenylphosphine Triphenylphosphine oxideNone 3-Dimethylaminopropyl-Olo-IM4 BP1diphenylphosphine oxide (Z)-11-[3-Dimethylamino-Olopropylidene]-6,11-dihydro-dibenz[b,e]oxepin-2-acetic acidOlopatadine (E)-11-[3-Dimethylamino-Olo-BP1propylidene]-6,11-dihydro-dibenz[b,e]oxepin-2-acetic acid (Z)-11-[3-Dimethylamino-Olo-HBrpropylidene]-6,11-dihydro-dibenz[b,e]oxepin-2-acetic acidhydrobromide (Z)-11-[3-Dimethylamino-Olo-HClpropylidene]-6,11-dihydro-dibenz[b,e]oxepin-2-acetic acidhydrochloride